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BACKGROUND: Children and adolescents with type 1 diabetes require frequent outpatient evaluation to assess glucose trends, modify insulin doses, and screen for comorbidities. Continuous glucose monitoring (CGM) provides a detailed glycemic control assessment. Telemedicine has been increasingly used since the COVID-19 pandemic. OBJECTIVE: To investigate CGM profile parameter improvement immediately following pediatric outpatient diabetes visits and determine if visit modality impacted these metrics, completion of screening laboratory tests, or diabetic emergency occurrence. METHODS: A dual-center retrospective review of medical records assessed the CGM metrics time in range and glucose management indicator for pediatric outpatient diabetes visits during 2021. Baseline values were compared with those at 2 and 4 weeks post visit. Rates of completion of screening laboratory tests and diabetic emergencies following visits were determined. RESULTS: A total of 269 outpatient visits (41.2% telemedicine) were included. Mean time in range increased by 1.63% and 1.35% at 2 and 4 weeks post visit (P=.003 and .01, respectively). Mean glucose management indicator decreased by 0.07% and 0.06% at 2 and 4 weeks post visit (P=.003 and .02, respectively). These improvements in time in range and glucose management indicator were seen across both telemedicine visits and in-person visits without a significant difference. However, patients seen in person were 2.69 times more likely to complete screening laboratory tests (P=.03). Diabetic emergencies occurred too infrequently to analyze. CONCLUSIONS: Our findings demonstrate an immediate improvement in CGM metrics following outpatient visits, regardless of modality. While statistically significant, the magnitude of these changes was small; hence, multiple visits over time would be required to achieve clinically relevant improvement. However, completion of screening laboratory tests was found to be more likely after visits occurring in person. Therefore, we suggest a hybrid approach that allows patient convenience with telemedicine but also incorporates periodic in-person assessment.

Investigative leads are not generated by traditional forensic DNA testing, if the source of the forensic evidence or a 1st degree relative of unidentified human remains is not in the DNA database. In such cases, forensic genetic genealogy (FGG) can provide valuable leads. However, FGG generated genetic data contain private and sensitive information. Therefore, it is essential to deploy approaches that minimize unnecessary disclosure of these data to mitigate potential risks to individual privacy. We recommend protective practices that need not impact effective reporting of relationship identifications. Examples include performing one-to-one comparisons of DNA profiles of third-party samples and evidence samples offline with an “air gap” to the internet and shielding the specific shared single nucleotide polymorphisms (SNP) states and locations by binning adjacent SNPs in forensic reports. Such approaches reduce risk of unwanted access to or reverse engineering of third-party individuals’ genetic data and can give these donors greater confidence to support use of their DNA profiles in FGG investigation.

Fasting mimicking diets (FMDs) are effective in the treatment of many solid tumors in mouse models, but their effect on hematologic malignancies is poorly understood, particularly in combination with standard therapies. Here we show that cycles of a 3-day FMD given to high-fat-diet-fed mice once a week increased the efficacy of vincristine to improve survival from BCR-ABL B acute lymphoblastic leukemia (ALL). In mice fed a standard diet, FMD cycles in combination with vincristine promoted cancer-free survival. RNA seq and protein assays revealed a vincristine-dependent decrease in the expression of multiple autophagy markers, which was exacerbated by the fasting/FMD conditions. The autophagy inhibitor chloroquine could substitute for fasting/FMD to promote cancer-free survival in combination with vincristine. In vitro, targeted inhibition of autophagy genes ULK1 and ATG9a strongly potentiated vincristines toxicity. Moreover, anti-CD8 antibodies reversed the effects of vincristine plus fasting/FMD in promoting leukemia-free survival in mice, indicating a central role of the immune system in this response. Thus, the inhibition of autophagy and enhancement of immune responses appear to be mediators of the fasting/FMD-dependent cancer-free survival in ALL mice.

Not available.

The Myelodysplastic syndromes (MDS) are a heterogenous group of clonal bone marrow (BM) stem cell myeloid neoplasms, characterized by bone marrow (BM) dysplasia, macrocytic anemia or cytopenia with a tendency for leukemic transformation. The suspicion of MDS is raised by a typical but not specific clinical picture and routine labs, but the gold standard for MDS diagnosis is still BM examination with the presence of uni-or multi-lineage dysplasia and blast percentage, together with exclusion of other reasons. Cytogenetics is also a part of the diagnostic process. Flow cytometry and genetics are helpful but are not always mandatory for MDS diagnosis. This review summarizes the current steps in the diagnostic approach for a patient suspected of having MDS. We also describe new concepts that use non-invasive diagnostic technologies, especially digital methods as well as peripheral blood genetics. The hope is that one day these will mature, be introduced into clinical practice, and perhaps in many cases even replace the invasive BM biopsy.

BackgroundChildren and adolescents with type 1 diabetes require frequent outpatient evaluation to assess glucose trends, modify insulin doses, and screen for comorbidities. Continuous glucose monitoring (CGM) provides a detailed glycemic control assessment. Telemedicine has been increasingly used since the COVID-19 pandemic. ObjectiveTo investigate CGM profile parameter improvement immediately following pediatric outpatient diabetes visits and determine if visit modality impacted these metrics, completion of screening laboratory tests, or diabetic emergency occurrence. MethodsA dual-center retrospective review of medical records assessed the CGM metrics time in range and glucose management indicator for pediatric outpatient diabetes visits during 2021. Baseline values were compared with those at 2 and 4 weeks post visit. Rates of completion of screening laboratory tests and diabetic emergencies following visits were determined. ResultsA total of 269 outpatient visits (41.2% telemedicine) were included. Mean time in range increased by 1.63% and 1.35% at 2 and 4 weeks post visit (P=.003 and .01, respectively). Mean glucose management indicator decreased by 0.07% and 0.06% at 2 and 4 weeks post visit (P=.003 and .02, respectively). These improvements in time in range and glucose management indicator were seen across both telemedicine visits and in-person visits without a significant difference. However, patients seen in person were 2.69 times more likely to complete screening laboratory tests (P=.03). Diabetic emergencies occurred too infrequently to analyze. ConclusionsOur findings demonstrate an immediate improvement in CGM metrics following outpatient visits, regardless of modality. While statistically significant, the magnitude of these changes was small; hence, multiple visits over time would be required to achieve clinically relevant improvement. However, completion of screening laboratory tests was found to be more likely after visits occurring in person. Therefore, we suggest a hybrid approach that allows patient convenience with telemedicine but also incorporates periodic in-person assessment.

Recruitment and retention are challenges for prospective pediatric cohort studies, particularly those involving serial venipunctures. We investigated factors underlying enrollment and retention in the Pandemic Response Repository through Microbial and Immune Surveillance and Epidemiology (PREMISE) Enterovirus D68 (EV-D68) Pilot Study, a multicenter prospective longitudinal cohort study assessing the utility of immunologic surveillance for pandemic preparedness. This study enrolls children ≤10 years for two blood draws, pre- and post-EV-D68 season, separated by 6–18 months. Overall, 174 children were enrolled in Cohort 1 of the study and 120 (69 %) of children completed the study, with follow-up blood samples obtained from 101 (58 %) of participants. Families were primarily motivated to participate by a desire to help other children, advance science, and better prepare for the next pandemic. Adding research blood draws to clinically indicated blood draws improved enrollment, and multiple study touch points facilitated retention. These findings can be applied to improve recruitment and retention in future pandemic preparedness efforts and longitudinal pediatric cohort studies.

This paper analyses Latin America’s role in an international system in flux, with high levels of uncertainty and transformations that signal a shift in the geoeconomic and geopolitical landscape across the world. Against this backdrop, the paper examines the challenges (both old and new) the region must face, focusing on the impact of global changes on regional dynamics and the capacity of the different countries to find answers both to the international situation and old and new internal problems. In addition, as an introductory paper to this monograph entitled “Geopolitics from Latin America: a change of cycle and multipolarity”, it identifies the fulcrums of these changes, their impact, the main actors involved and the processes underway.

ObjectiveThis randomized clinical trial tested the effectiveness of an addiction-based digital weight-loss intervention, focusing on withdrawal/abstinence from self-identified problem foods, snacking and excessive amounts at meals, and discomfort displacement, with and without coaching, compared to an in-person, multi-disciplinary, care model among adolescents with obesity. We hypothesized that the digital intervention with coaching would yield greater weight loss and lower delivery burden than the standard clinical arm, and greater participant engagement than the digital arm without coaching.MethodsAdolescents were randomized to app intervention, with or without coaching, or in-person multidisciplinary obesity intervention for 6 months. The primary outcome was change in %BMIp95 at weeks 12 and 24. A mixed-effects linear regression model was used to assess the association between change in %BMIp95 and intervention arm. We were also interested in assessing delivery burden, participant engagement and evaluating the relationships between weight change and demographic characteristics, mood, executive function and eating behaviours.ResultsAll adolescents (n = 161; BMI ≥95th%, age 16 ± 2.5 year; 47% Hispanic, 65% female, 59% publicly insured) lost weight over 24-weeks (-1.29%, [-1.82, -0.76], p

The Myelodysplastic syndromes (MDS) are a heterogenous group of clonal bone marrow (BM) stem cell myeloid neoplasms, characterized by ineffective hematopoiesis that results in dysplasia in hematopoietic cells and peripheral cytopenias, especially anemia, and a propensity to leukemic transformation. The suspicion of MDS is raised by a typical but not specific clinical picture and routine laboratory findings, but the gold standard for MDS diagnosis is still BM examination with the presence of uni-or multi-lineage dysplasia and increased blast percentage, together with exclusion of other reasons. Cytogenetics is also an essential part of the diagnostic and prognostic processes. Flow cytometry and full genetic characterization are helpful but not mandatory for MDS diagnosis. This review summarizes the current steps of diagnostic approach for a patient suspected of having MDS. We also express our hopes that within the near future, non-invasive technologies, especially digital and peripheral blood genetics, will mature and be introduced into practice.

In the current landscape of higher education, the quality of teaching plays a crucial role in supporting the comprehensive development of students. To ensure the effectiveness of the learning process, evaluating lecturers based on student opinions is an essential means of providing feedback and optimizing the learning experience. This paper focuses on constructing a lecturer ranking system, particularly in the context of a specific course through the evaluation process from students. Four different methods were employed to assess lecturers, including the PSI method, SRP method, RAM method, and PIV method. The evaluation results using these four methods were compared with each other and also with the traditional evaluation approach currently utilized in the educational institution. The achieved results demonstrate that the approach outlined in this paper is highly suitable for determining the rankings of lecturers when teaching individual courses.

Este artículo analiza el desenvolvimiento del Partido Comunista argentino (PC) en relación con las luchas femeninas dentro del ámbito de la reproducción social durante la aplicación de su orientación de Frente Popular, entre 1935 y 1946. Los estudios sobre esta etapa se han centrado en observar su acción entre las mujeres trabajadoras sindicalizadas o en su estímulo a la creación de organizaciones “amplias” vinculadas a la lucha “antifascista”. Aquí proponemos un ángulo diferente y poco explorado: el de sus lazos con aquellas luchas por la carestía de la vida, el acceso al agua o la defensa de las ferias donde se conseguían precios más baratos, mayormente encabezadas por mujeres de las familias proletarias. La apelación tradicional al “maternalismo” y al rol moralizante de las mujeres dentro de la familia, también se transformó en un motor para la acción política a la cual, con contradicciones, el comunismo buscó ligarse.

Revisión del libro El nudo gordiano. El Partido Socialista argentino y el movimiento obrero en los años treinta por D. Ceruso

In addition to the significant role in physical activity, skeletal muscle also contributes to health through the storage and use of macronutrients associated with energy homeostasis. However, the mechanisms of regulating integrated metabolism in skeletal muscle are not well-defined. Here, we compared the skeletal muscle transcriptome from obese and lean control subjects in different species (human and mouse) and found that interferon regulatory factor 4 (IRF4), an inflammation-immune transcription factor, conservatively increased in obese subjects. Thus, we investigated whether IRF4 gain of function in the skeletal muscle predisposed to obesity and insulin resistance. Conversely, mice with specific IRF4 loss in skeletal muscle showed protection against the metabolic effects of high-fat diet, increased branched-chain amino acids (BCAA) level of serum and muscle, and reprogrammed metabolome in serum. Mechanistically, IRF4 could transcriptionally upregulate mitochondrial branched-chain aminotransferase (BCATm) expression; subsequently, the enhanced BCATm could counteract the effects caused by IRF4 deletion. Furthermore, we demonstrated that IRF4 ablation in skeletal muscle enhanced mitochondrial activity, BCAA, and fatty acid oxidation in a BCATm-dependent manner. Taken together, these studies, for the first time, established IRF4 as a novel metabolic driver of macronutrients via BCATm in skeletal muscle in terms of diet-induced obesity.

Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here, we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with downregulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll-like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a potentially novel metabolic immune checkpoint.

Installing photovoltaic (PV) collectors above arable land (Agrivoltaics) can aid with the shortage of available land area for solar power generation and food production. Most open field agrivoltaics are based on opaque PV devices which absorb photosynthetically active radiation (PAR, 400-700 nm), reducing crop yield and increasing variability in light distribution across the field. This research evaluates the performance of spectral beam splitter integrated photovoltaic (BSIPV) modules using a PV performance model. A high percentage (66 %) of PAR incident on the spectral beam splitter is transmitted effectively to the plants, while the near infrared radiation (NIR, > 700 nm) is reflected to the adjacent bifacial opaque photovoltaic module to generate power. In the model, seven rows of modules were placed uniformly across the field at a height of four meters from the ground. Considering a cool season (November – March) in Yuma, Arizona, in a conventional opaque PV agrivoltaic farm received 43 % lower total daylight integral (TDLI) across the season in comparison to open field with a coefficient of variation (ratio of standard deviation to mean expressed in percentage) of 56 % in TDLI across the field. On the other hand, the BSIPV agrivoltaic farm limited the drop in TDLI to 7 % in comparison to open field and the coefficient of variation to 14 % across the field. Thus, BSIPV showed a 36 % improvement in TDLI relative to the conventional opaque PV agrivoltaic farm. The results of the current study justify further research on the proposed collector concept.

ObjectiveWe designed an mHealth application (app) user interface (UI) prototype informed by participatory design sessions, persuasive systems design (PSD) principles, and Lorig and Holman's self-management behavior framework to support self-management activities of Hispanic informal dementia caregivers and assessed their perceptions and preferences regarding features and functions of the app.Materials and methodsOur observational usability study design employed qualitative methods and forced choice preference assessments to identify: (1) the relationship between user preferences for UI features and functions and PSD principles and (2) user preferences for UI design features and functions and app functionality. We evaluated 16 pairs of mHealth app UI prototype designs. Eight paper-based paired designs were used to assess the relationship between PSD principles and caregiver preferences for UI features and functions to support self-management. An Apple iPad WIFI 32GB was used to display another 8 paired designs and assess caregiver preferences for UI functions to support the self-management process.ResultsCaregivers preferred an app UI with features and functions that incorporated a greater number of PSD principles and included an infographic to facilitate self-management. Moreover, caregivers preferred a design that did not depend on manual data entry, opting instead for functions such as drop-down list, drag-and-drop, and voice query to prioritize, choose, decide, and search when performing self-management activities.ConclusionOur assessment approaches allowed us to discern which UI features, functions, and designs caregivers preferred. The targeted application of PSD principles in UI designs holds promise for supporting personalized problem identification, goal setting, decision-making, and action planning as strategies for improving caregiver self-management confidence.

BackgroundObesity is a significant contributor to breast cancer recurrence and mortality. A central mechanism by which obesity stimulates cancer progression is through chronic, low-grade inflammation in adipose tissue. Exercise interventions to target chronic inflammation has a potential to improve obesity- and breast cancer-related outcomes; however, no studies have investigated the roles of exercise in modulating adipose tissue inflammation in breast cancer survivors. Also, it is unclear which exercise prescription would be optimal to maximize the outcomes. Therefore, we designed a randomized controlled trial (Taking AIM at Breast Cancer: Targeting Adiposity and Inflammation with Movement to Improve Prognosis in Breast Cancer Survivors [AIM] Trial) to examine the mechanisms by which different modalities of exercise impact chronic inflammation as a biomarker of breast cancer prognosis.MethodsThe AIM trial is a prospective, three-armed, phase II randomized controlled trial investigating the effects of a 16-week supervised circuit aerobic and resistance exercise (CARE) program versus a traditional aerobic and resistance exercise (TARE) program and attention control (AC) on adipose tissue inflammation in breast cancer survivors. 276 patients who are diagnosed with stage 0-III breast cancer, post-treatment, sedentary, and centrally obese are randomized to one of the three groups. The CARE and TARE groups participate in thrice-weekly supervised exercise sessions for 16 weeks. The AC group are offered the CARE program after the intervention period. The primary endpoint is adipose tissue inflammation assessed by core biopsy and blood draw. The secondary and tertiary endpoints are sarcopenic obesity, physical fitness and function, and patient reported outcomes. The exploratory outcomes are long-term breast cancer outcomes.DiscussionThis is the first randomized controlled trial examining the effects of exercise on adipose tissue inflammation in obese, breast cancer survivors. Our findings are anticipated to contribute to a better understanding of exercise modalities and mechanisms on adipose tissue inflammation that can potentially improve breast cancer prognosis.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT03091842 identifier [NCT#03091842].

With the development of agricultural production, the demand for electricity correspondingly increases. To sustainably meet this demand, renewable energy sources (RESs) can be utilized. This paper explores the application of RES alternatives in agriculture to provide guidelines for enhancing sustainable agricultural practices in Bosnia and Herzegovina. The study employs expert decision making using fuzzy multi-criteria decision-making (MCDM) methods. A decision-making model incorporating nine criteria and six alternatives was developed. Using the direct weight calculation (DiWeC) approach, the findings indicate that economic criteria are prioritized over other sustainability criteria. The results from the fuzzy RAWEC (ranking of alternatives with weights of criteria) method reveal that solar energy has the greatest potential for advancing sustainable agricultural production in Bosnia and Herzegovina. For practical implementation of RES alternatives, active involvement from state institutions and local communities is essential.

Abstract Eltrombopag has been previously shown to be effective in reversing azacitidine‐mediated thrombocytopenia. This was further investigated in the SUPPORT trial, a phase III study assessing the efficacy/safety of eltrombopag plus azacitidine in patients with intermediate‐ to high‐risk myelodysplastic syndromes and thrombocytopenia. The results did not support a clinical benefit for the addition of eltrombopag to azacitidine. We investigated if the somatic mutational profiles in the patient cohort were associated with treatment outcomes. Based on the available data, we observed no imbalance in the mutational profiles between treatment arms or a clear association between identified somatic mutations and clinical outcomes.

PurposeThe objective of this study is to explore the impact of artificial intelligence (AI) development on the sports industry labor market, the ways in which AI has influenced the demand for labor, created new job opportunities, and impacted existing job roles.MethodologyIt refers to the inductive approach in the spirit technological determinism theory. It is based on the literature review and written qualitative, semi-structured interviews (N = 14) with sports human resources, management, and technology professionals (purposive sampling). Analysis involved inductive coding and line-by-line analytics of the data.FindingsThe labor market implications of AI in the sports industry are multifaceted. New job roles are likely to emerge, demanding a blend of AI expertise, data-analysis skills, and sports domain knowledge. Professionals in roles such as sports data analysts and marketing experts may find increasing opportunities. However, certain jobs undergo transformation as AI automates routine tasks. It requires individuals to upskill or transition to roles that require a deeper understanding of AI. This necessitates the creation of responsibilities focused on ethical AI governance and oversight.OriginalityIt is important to research the impact of AI dissemination on the sports industry labor market in a holistic manner because the effects of AI are complex and far-reaching. While there are potential benefits to the implementation of AI, there are also potential risks and challenges that need to be addressed, the implementation of AI in the sports industry could have broader social and ethical implications that need to be considered.

Abstract Endothelial progenitor cells are increasingly being studied in various diseases ranging from ischemia, diabetic retinopathy, and in cancer. The discovery that these cells can be mobilized from their bone marrow niche to sites of inflammation and tumor to induce neovasculogenesis has afforded a novel opportunity to understand the tissue microenvironment and specific cell-cell interactive pathways. This review provides a comprehensive up-to-date understanding of the physiological function and therapeutic utility of these cells. The emphasis is on the systemic factors that modulate their differentiation/mobilization and survival and presents the challenges of its potential therapeutic clinical utility as a diagnostic and prognostic reagent.

Mitochondrial respiration is critical for cell proliferation. In addition to producing ATP, respiration generates biosynthetic precursors, such as aspartate, an essential substrate for nucleotide synthesis. Here, we show that in addition to depleting intracellular aspartate, electron transport chain (ETC) inhibition depletes aspartate-derived asparagine, increases ATF4 levels, and impairs mTOR complex I (mTORC1) activity. Exogenous asparagine restores proliferation, ATF4 and mTORC1 activities, and mTORC1-dependent nucleotide synthesis in the context of ETC inhibition, suggesting that asparagine communicates active respiration to ATF4 and mTORC1. Finally, we show that combination of the ETC inhibitor metformin, which limits tumor asparagine synthesis, and either asparaginase or dietary asparagine restriction, which limit tumor asparagine consumption, effectively impairs tumor growth in multiple mouse models of cancer. Because environmental asparagine is sufficient to restore tumor growth in the context of respiration impairment, our findings suggest that asparagine synthesis is a fundamental purpose of tumor mitochondrial respiration, which can be harnessed for therapeutic benefit to cancer patients.

Being overweight or obese (OW/OB) during B-cell acute lymphoblastic leukemia (B-ALL) induction is associated with chemoresistance as quantified by minimal residual disease (MRD). We hypothesized that caloric and nutrient restriction from diet/exercise could lessen gains in fat mass (FM) and reduce postinduction MRD. The Improving Diet and Exercise in ALL (IDEAL) trial enrolled patients 10 to 21 years old, newly diagnosed with B-ALL (n = 40), in comparison with a recent historical control (n = 80). Designed to achieve caloric deficits ≥20% during induction, reduce fat intake/glycemic load, and increase activity, IDEAL's end points were FM gain (primary), MRD ≥0.01%, and adherence/feasibility. Integrated biology explored biomarkers of OW/OB physiology. IDEAL intervention did not significantly reduce median FM change from baseline overall (+5.1% [interquartile range [IQR], 15.8] vs +10.7% [IQR, 16.0]; P = .13), but stratified analysis showed benefit in those OW/OB (+1.5% [IQR, 6.6] vs +9.7% [IQR, 11.1]; P = .02). After accounting for prognostic factors, IDEAL intervention significantly reduced MRD risk (odds ratio, 0.30; 95% confidence interval, 0.09-0.92; P = .02). The trial exceeded its adherence (≥75% of overall diet) and feasibility (≥80% completed visits) thresholds. Integrated biology found the IDEAL intervention increased circulating adiponectin and reduced insulin resistance. The IDEAL intervention was feasible, decreased fat gain in those OW/OB, and reduced MRD. This is the first study in any hematologic malignancy to demonstrate potential benefit from caloric restriction via diet/exercise to augment chemotherapy efficacy and improve disease response. A prospective, randomized trial is warranted for validation. These trials were registered at www.clinicaltrials.gov as #NCT02708108 (IDEAL trial) and #NCT01317940 (historical control).

BackgroundThere is increasing evidence that adipocytes play an active role in the cancer microenvironment. We have previously reported that adipocytes interact with acute lymphoblastic leukemia (ALL) cells, contributing to chemotherapy resistance and treatment failure. In the present study, we investigated whether part of this resistance is due to adipocyte provision of lipids to ALL cells.MethodsWe cultured 3T3-L1 adipocytes, and tested whether ALL cells or ALL-released cytokines induced FFA release. We investigated whether ALL cells took up these FFA, and using fluorescent tagged BODIPY-FFA and lipidomics, evaluated which lipid moieties were being transferred from adipocytes to ALL. We evaluated the effects of adipocyte-derived lipids on ALL cell metabolism using a Seahorse XF analyzer and expression of enzymes important for lipid metabolism, and tested whether these lipids could protect ALL cells from chemotherapy. Finally, we evaluated a panel of lipid synthesis and metabolism inhibitors to determine which were affected by the presence of adipocytes.ResultsAdipocytes release free fatty acids (FFA) when in the presence of ALL cells. These FFA are taken up by the ALL cells and incorporated into triglycerides and phospholipids. Some of these lipids are stored in lipid droplets, which can be utilized in states of fuel deprivation. Adipocytes preferentially release monounsaturated FFA, and this can be attenuated by inhibiting the desaturating enzyme steroyl-CoA decarboxylase-1 (SCD1). Adipocyte-derived FFA can relieve ALL cell endogenous lipogenesis and reverse the cytotoxicity of pharmacological acetyl-CoA carboxylase (ACC) inhibition. Further, adipocytes alter ALL cell metabolism, shifting them from glucose to FFA oxidation. Interestingly, the unsaturated fatty acid, oleic acid, protects ALL cells from modest concentrations of chemotherapy, such as those that might be present in the ALL microenvironment. In addition, targeting lipid synthesis and metabolism can potentially reverse adipocyte protection of ALL cells.ConclusionThese findings uncover a previously unidentified interaction between ALL cells and adipocytes, leading to transfer of FFA for use as a metabolic fuel and macromolecule building block. This interaction may contribute to ALL resistance to chemotherapy, and could potentially be targeted to improve ALL treatment outcome.

Introduction: Despite the burdens that resident attrition places upon programs and fellow trainees, emergency medicine (EM) as a specialty has only begun to explore the issue. Our primary objectives were to quantify attrition in EM residency programs and elucidate the reasons behind it. Our secondary objectives were to describe demographic characteristics of residents undergoing attrition, personal factors associated with attrition, and methods of resident replacement.Methods: We conducted a national survey study of all EM program directors (PDs) during the 2018-2019 academic year. PDs were asked to identify all residents who had left their program prior to completion of training within the last four academic years (2015-2016 to 2018-2019), provide relevant demographic information, select perceived reasons for attrition, and report any resident replacements. Frequencies, percentages, proportions, and 95% confidence intervals were obtained for program- and resident-specific demographics. We performed Fisher’s exact tests to compare reasons for attrition between age groups.Results: Of 217 PDs successfully contacted, 118 completed the questionnaire (response rate of 54%). A third of programs (39 of 118) reported at least one resident attrition. A total of 52 residents underwent attrition. Attrition was most likely to occur prior to completion of two years of training. Gender and underrepresented minority status were not associated with attrition. Older residents were more likely to leave due to academic challenges. The most common reported reason for attrition was to switch specialties. Resident replacement was found in 42% of cases.Conclusion: One-third of programs were affected by resident attrition. Gender and underrepresented minority status were not associated with attrition.

Abstract Background Although described by Hippocrates in 400 B.C., pemphigus disease still needs a safe therapeutical approach, given that the currently used therapies (i.e. corticosteroids and immunosuppressive drugs) often provoke collateral effects. Here we present preliminary data on the possible use of a proteomics derived desmoglein peptide which appears promising in halting disease progression without adverse effects. Methods The low-similarity Dsg349–60REWVKFAKPCRE peptide was topically applied for 1 wk onto a lesion in a patient with a late-stage Pemphigus vulgaris (PV) complicated by diabetes and cataract disease. The peptide was applied as an adjuvant in combination with the standard corticosteroid-based immunosuppressive treatment. Results After 1 wk, the treated PV eroded lesion appeared dimensionally reduced and with an increased rate of re-epithelization when compared to adjacent non-treated lesions. Short-term benefits were: decrease of anti-Dsg antibody titer and reduction of the corticosteroid dosage. Long-term benefits: after two years following the unique 1-wk topical treatment, the decrease of anti-Dsg antibody titer persists. The patient is still at the low cortisone dosage. Adverse effects: no adverse effect could be monitored. Conclusion With the limits inherent to any preliminary study, this case report indicates that topical treatment with Dsg349–60REWVKFAKPCRE peptide may represent a feasible first step in the search for a simple, effective and safe treatment of PV.

Abstract Background A number of autoimmune diseases have been clinically and pathologically characterized. In contrast, target antigens have been identified only in a few cases and, in these few cases, the knowledge of the exact epitopic antigenic sequence is still lacking. Thus the major objective of current work in the autoimmunity field is the identification of the epitopic sequences that are related to autoimmune reactions. Our labs propose that autoantigen peptide epitopes able to evoke humoral (auto)immune response are defined by the sequence similarity to the host proteome. The underlying scientific rationale is that antigen peptides acquire immunoreactivity in the context of their proteomic similarity level. Sequences uniquely owned by a protein will have high potential to evoke an immune reaction, whereas motifs with high proteomic redundancy should be immunogenically silenced by the tolerance phenomenon. The relationship between sequence redundancy and peptide immunoreactivity has been successfully validated in a number of experimental models. Here the hypothesis has been applied to pemphigus diseases and the corresponding desmoglein autoantigens. Methods Desmoglein 3 sequence similarity analysis to the human proteome followed by dot-blot/NMR immunoassays were carried out to identify and validate possible epitopic sequences. Results Computational analysis led to identifying a linear immunodominant desmoglein-3 epitope highly reactive with the sera from Pemphigus vulgaris as well as Pemphigus foliaceous. The epitopic peptide corresponded to the amino acid REWVKFAKPCRE sequence, was located in the extreme N-terminal region (residues 49 to 60), and had low redundancy to the human proteome. Sequence alignment showed that human desmoglein 1 and 3 share the REW-KFAK–RE sequence as a common motif with 75% residue identity. Conclusion This study 1) validates sequence redundancy to autoproteome as a main factor in shaping desmoglein peptide immunogenicity; 2) offers a molecular mechanicistic basis in analyzing the commonality of autoimmune responses exhibited by the two forms of pemphigus; 3) indicates possible peptide-immunotherapeutical approaches for pemphigus diseases.

This study sought to determine the perceived benefits of the Residential Care Transition Module (RCTM), a novel multi-component, psychoeducational/psychosocial, telehealth intervention for caregivers of cognitively impaired relatives living in residential long-term care (RLTC). Few support programs exist for these caregivers. Determining the intervention’s mechanisms of benefit will provide actionable clinical and research information regarding which key features aspects RLTC and public health agencies should offer their families. We conducted semi-structured interviews with 30 purposively selected participants randomly assigned to receive the RCTM. Additionally, an open-ended survey question solicited feedback at 4 (n = 90), 8 (n = 79), and 12 months (n = 77). Available qualitative data were analyzed for thematic content. Participants endorsed 9 mechanisms of benefit. Six mechanisms were related to RCTM content: education dementia progression and dementia behavior management, personalized resource provision, strategies for communication and engagement with the care recipient (CR) and others, management of multiple roles, and relaxation exercises. Three mechanisms were related to coaching: emotional support, knowledgeability, and being a neutral third party. Common benefits attributed to RCTM included improvement in mood, caregiving confidence, and communication and interactions with CR and others. Using qualitative data and analyses, we discovered the most valued aspects of the RCTM intervention. These mechanisms of benefit have not been described in the literature. Notably, we were unable to detect mechanisms of benefit in a separate analysis utilizing quantitative data. Findings emphasize the importance of including qualitative measures in intervention research and selecting quantitative measures that reflect the intervention’s real effects, if any.